As a radiochemist, I find rewarding the development of facile
synthetic methodologies for the preparation of radiopharmaceuticals
which incorporate the short half-life C-11 and F-18 radionuclides that
are frequently employed for PET imaging. In particular, synthesis of
C-11 radiopharmaceuticals is very challenging in that it generally has
to be accomplished inside 60 minutes in order to possess adequate
radioactivity for PET imaging.
Improving overall binding properties of existing radioligands and the
development of new ligands comprise my imaging interest in the areas of
CNS and oncology. For CNS, I am interested in developing
radiopharmaceuticals that can be employed for early diagnosis of
Alzheimer and Parkinson diseases and which can lead to development of
better treatments. Another interesting area, FAAH (fatty acid amide
hydrolase) has emerged as a novel therapeutic target for a range of
clinical disorders. It is a membrane-bound intracellular serine
hydrolase that is responsible for AEA (Anandamide, an endogenous
cannabinoid) metabolism. Indeed, FAAH has been targeted as biomarker of
AEA which is known to modulate several physiological processes in both
peripheral and nervous system. FAAH inactivation produces proactive
subset of behavioral effects similar to that observed for direct CB1
agonists, but without inducing analogous side-effects. To date, all
evidence suggests that compounds which increase the tone of AEA, whether
blocking its transport or inhibiting its metabolism, are
therapeutically valuable for treatment. Accordingly imaging FAAH should
accelerate validation of FAAH inhibitors as therapeutic targets.
Small-molecule radiotracers not only would provide valuable research
tools for further understanding of this and other therapeutic targets,
but also allows fast validation of efficacy and selectivity of potential
drug inhibitors as well. The potential disorders which can benefit from
targeted enhancement of AEA include analgesic, anti tumor and neuroprotection.
Regarding oncology, there is a dire need for radiotracers which are
capable of early detection of pancreatic cancer. It is the second most
common gastrointestinal malignancy in the USA. Meanwhile, peptide
transporters are important drug delivery targets and growing number of
studies have been reported on regulation of their transport capacity.
Tumor cells have been shown to up-regulate the expression of the peptide
transporter type PepT1, and high levels of this transporter have been
found in variety of cancer cells, including pancreatic. Thus, increased
expression of PepT1 in the cellular membrane of cancer cells has been
investigated as a possible target for delivery of peptidomimetic
anti-cancer drugs as well as prodrugs. Bestatin, a leukotriene A4
hydrolase inhibitor, is among the peptidomimetic PepT1 substrates which
have been shown to have anticancer activity towards non-lymphocytic
leukemia as well as pancreatic adenocarcinoma. In this regard, I am
interested in developing radiotracers that are substrates of the peptide
transporter PepT1 for imaging pancreatic cancer. Alternatively,
inhibition of PepT1 activity has also been suggested as a novel
chemotherapy approach. With this in mind, radiotracers that are
substrates for PepT1 should also facilitate the development of PepT1
inhibitors.